1. Technical Field of the Invention
The present invention relates to novel compositions of inverse emulsion type comprising at least one compound from the family of the avermectins, preferably ivermectin, and topical pharmaceutical compositions comprised thereof for the treatment of rosacea.
2. Description of Background and/or Related and/or Prior Art
Ivermectin is a mixture of two compounds belonging to the class of the avermectins, 5-O-demethyl-22,23-dihydroavermectin A1a and 5-O-demethyl-22,23-dihydroavermectin A1b. They are also known under the trademarks of 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b. Ivermectin comprises at least 80% of 22,23-dihydroavermectin B1a and less than 20% of 22,23-dihydroavermectin B1b. This active agent forms part of the class of the avermectins, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds J. E. F. (Ed), (1993) Martindale, The Extra Pharmacopoeia, 29th Edition, Pharmaceutical Press, London).
In the middle of the 1980s, ivermectin was presented as a broad-spectrum anti-parasitic medicament for veterinary use (Campbell W. C. et al. (1983), “Ivermectin: a potent new anti-parasitic agent,” Science, 221, 823-828). It is effective against the majority of common intestinal worms (except for the Teniae), the majority of the acarids and a few lice. It exhibits in particular a high affinity for the glutamate-dependent chloride channels present in the nerve and muscle cells of invertebrates. Its attachment to these channels promotes an increase in the membrane permeability to chloride ions, resulting in hyperpolarization of the nerve or muscle cell. This results in neuromuscular paralysis, which can bring about the death of certain parasites. Ivermectin also interacts with other ligand-dependent chloride channels, such as those involving the GABA (γ-aminobutyric acid) neuromediator.
Ivermectin is more particularly an anthelmintic. It has been described in man in the treatment of onchocerciasis due to Onchocerca volvulus, of gastrointestinal strongyloidiasis (anguillulosis) (product Stromectol®) and of human scabies (Meinking T. L. et al., N. Enql. J. Med., 1995, Jul., 6, 333(1), 26-30, The treatment of scabies with ivermectin) and in the treatment of microfilaremia diagnosed or suspected in subjects affected by lymphatic filariasis due to Wuchereria bancroffi. 
U.S. Pat. No. 6,133,310 describes the administration of ivermectin topically, in the form of a prototype of a lotion constituted of a mixture of ivermectin and of water, and also mentions the possibility of a prototype of a cream constituted, for its part, of the mixture of ivermectin and of an excipient, such as propylene glycol or sodium lauryl sulfate, but does not describe any pharmaceutical composition as such. These mixtures are similar to experimental preparations employed in the context of first results of a proof of concept. Specifically, the disclosure in this patent does not teach one skilled in the art anything regarding the feasibility of industrially acceptable pharmaceutical compositions comprising ivermectin, in particular having a good cosmetic quality and a lifetime sufficient for an industrial pharmaceutical product (minimum 2 years).
The ivermectin according to the present invention comprises at least 80% of 22,23-dihydroavermectin B1a and less than 20% of 22,23-dihydroavermectin B1b.
Ivermectin is highly unstable in the presence of water and it proves to be particularly difficult to obtain stable pharmaceutical compositions comprising ivermectin. It exhibits the difficulty of being very sparingly soluble and rarely stable in the cosmetic or pharmaceutical solvents commonly employed, in particular water; specifically, it is sensitive to an aqueous environment. This sensitivity to water can result in chemical instability of the active principle and/or in crystallization of the initially dissolved active principle. This sensitivity to water thus limits its formulation in cosmetic or dermatological compositions administered via the topical or oral route.
The phenomena of chemical decomposition and/or of crystallization of ivermectin in the presence of water have as consequences a reduction in or loss of effectiveness and uncertainty with regard to the dose of active principle employed during the administration thereof, which militates against the desired objective. In addition, this decomposition of the active principle and/or its crystallization can modify the overall stability of the compositions and their appearance.
The pharmaceutical dosage form most commonly employed today in dermatology is the oil-in-water emulsion in which the active principle is preferably dissolved in the lipophilic phase. However, this solution remains rather unsatisfactory as, in order to meet an objective of concentration of active principle having a therapeutically quantifiable effectiveness, very high concentrations of solvating oils will be necessary, resulting in products which would without doubt be rather unpleasant to use, due to their sticky feel, and physically unstable, while remaining limited in concentration of active principle.
One possibility is to dissolve the active principle in the hydrophilic phase of the emulsion, within the limit of its solubility in aqueous or aqueous/glycolic media.
However, this solution does not make it possible to solve the problems of chemical stability encountered with ivermectin as the activity in water of the emulsion remains very high.
The replacement of all or part of the aqueous phase by one or more glycols generally results in formulations which are not very acceptable cosmetically. In particular, above 20% glycol, the formulation is not very acceptable cosmetically due to its sticky feel, and it is often not guaranteed to be physically stable.